Antibodies have played an essential role in biopharmaceutical research and drug discovery efforts for many decades. The utility of antibodies as therapeutic agents for the treatment of human diseases has been idealized for many years due to their: (a) long half-life in vivo; (b) ability to bind target(s) with high affinity and specificity; and (c) potential to mediate immune effector functions (such as complement fixation and antibody-dependent cellular cytotoxicity).
The reduction of the therapeutic antibody concept to practice was severely limited, however, until now, by the adverse immunogenicity of antibodies obtained from non-human species which restricted long-term clinical utility of the antibodies. Recent technological advances have provided new ways of overcoming these limitations by providing a means of obtaining fully human antibodies with less immunogenicity and a longer-term therapeutic potential. Additionally, developments in combinatorial library methods and antibody-engineering have opened opportunities for modification of antibody-affinity, half-life, and/or effector functions.
One such technology, which employs filamentous phage-displayed, combinatorial libraries of antibody fragments fused to the phage coat protein (so-called “phage displayed library”), has been effectively used to discover antibodies with high affinity, specificity, and agonistic or antagonistic acitivity in vivo.
Human interferon gamma (hIFNγ) is a lymphokine produced by activated T-lymphocytes and natural killer cells. It manifests antiproliferative, antiviral and immunomodulatory activites and binds to hIFNγ-R, a heterodimeric receptor on most primary cells of the immune system; Langer et al., Immunology Today, 9:393 (1988), and triggers a cascade of events leading to inflammation. The antiviral and immunomodulatory activity of IFNγ is known to have beneficial effects in a number of clinical conditions. However, there are many clinical settings in which IFNγ-activity is known to have deleterious effects. For example, autoimmune dieseases are associated with high levels of hIFNγ in the blood, and there is now evidence suggesting that sequestration of IFNγ is associated with symptomatic relief of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and multiple sclerosis (MS); see, e.g., Skurkovich et al., Intern. Journal of Immunotherapy, 14:23–32 (1998); Gerez et al., Clin. Exp. Immunol., 109:296–303 (1997). IFNγ-activity has also been linked to such disease states as cachexia, septic shock and Crohn's disease.
Because blocking the interaction of hIFNγ to its receptor represents the most upstream step of intervention in this regard, a fully human antibody with hIFNγ-neutralizing activity represents an attractive therapeutic product candidate. It is an object of the present invention to employ the phage displayed library technology to identify antibodies using human interferon-gamma (hIFNγ) as the therapeutic target.